tbuckley/cabot-search huggingface dataset:
Consent Laws for Minors Regarding Sexually Transmitted Infection and HIV Services
Authors: Charles G. Kels
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Unique roles of co-receptor-bound LCK in helper and cytotoxic T cells
Authors: Veronika Horkova, Ales Drobek, Darina Paprckova, Veronika Niederlova, Avishek Prasai, Valeria Uleri, Daniela Glatzova, Markus Kraller, Michaela Cesnekova, Sarka Janusova, Eva Salyova, Oksana Tsyklauri, Theresa A. Kadlecek, Katerina Krizova, René Platzer, Kilian Schober, Dirk H. Busch, Arthur Weiss, Johannes B. Huppa, Ondrej Stepanek
Journal: Nature Immunology (2022)

Abstract The kinase LCK and CD4/CD8 co-receptors are crucial components of the T cell antigen receptor (TCR) signaling machinery, leading to key T cell fate decisions. Despite decades of research, the roles of CD4–LCK and CD8–LCK interactions in TCR triggering in vivo remain unknown. In this study, we created animal models expressing endogenous levels of modified LCK to resolve whether and how co-receptor-bound LCK drives TCR signaling. We demonstrated that the role of LCK depends on the co-receptor to which it is bound. The CD8-bound LCK is largely dispensable for antiviral and antitumor activity of cytotoxic T cells in mice; however, it facilitates CD8 + T cell responses to suboptimal antigens in a kinase-dependent manner. By contrast, the CD4-bound LCK is required for efficient development and function of helper T cells via a kinase-independent stabilization of surface CD4. Overall, our findings reveal the role of co-receptor-bound LCK in T cell biology, show that CD4- and CD8-bound LCK drive T cell development and effector immune responses using qualitatively different mechanisms and identify the co-receptor–LCK interactions as promising targets for immunomodulation.
Association Between the 2021 Heat Wave in Portland, Oregon, and Seattle, Washington, and Emergency Department Visits
Authors: Amruta Nori-Sarma, Chad Milando, Kate R. Weinberger, Jeremy J. Hess, Nicole A. Errett, Gregory A. Wellenius
Journal: JAMA (2022)

This study used a health care claims data set of enrollees in commercial and Medicare Advantage insurance plans to assess the association between the June 2021 heat wave and the rates of emergency department visits in Portland, Oregon, and Seattle, Washington.
The Political Responsibility of the Physician
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Modeling resistance of colorectal peritoneal metastases to immune checkpoint blockade in humanized mice
Authors: Emre Küçükköse, Balthasar A Heesters, Julien Villaudy, André Verheem, Madalina Cercel, Susan van Hal, Sylvia F Boj, Inne H M Borel Rinkes, Cornelis J A Punt, Jeanine M L Roodhart, Jamila Laoukili, Miriam Koopman, Hergen Spits, Onno Kranenburg
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background The immunogenic nature of metastatic colorectal cancer (CRC) with high microsatellite instability (MSI-H) underlies their responsiveness to immune checkpoint blockade (ICB). However, resistance to ICB is commonly observed, and is associated with the presence of peritoneal-metastases and ascites formation. The mechanisms underlying this site-specific benefit of ICB are unknown. Methods We created a novel model for spontaneous multiorgan metastasis in MSI-H CRC tumors by transplanting patient-derived organoids (PDO) into the cecum of humanized mice. Anti-programmed cell death protein-1 (PD-1) and anti-cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) ICB treatment effects were analyzed in relation to the immune context of primary tumors, liver metastases, and peritoneal metastases. Immune profiling was performed by immunohistochemistry, flow cytometry and single-cell RNA sequencing. The role of B cells was assessed by antibody-mediated depletion. Immunosuppressive cytokine levels (interleukin (IL)-10, transforming growth factor (TGF)b1, TGFb2, TGFb3) were determined in ascites and serum samples by ELISA. Results PDO-initiated primary tumors spontaneously metastasized to the liver and the peritoneum. Peritoneal-metastasis formation was accompanied by the accumulation of ascites. ICB completely cleared liver metastases and reduced primary tumor mass but had no effect on peritoneal metastases. This mimics clinical observations. After therapy discontinuation, primary tumor masses progressively decreased, but peritoneal metastases displayed unabated growth. Therapy efficacy correlated with the formation of tertiary lymphoid structures (TLS)—containing B cells and juxtaposed T cells—and with expression of an interferon-γ signature together with the B cell chemoattractant CXCL13. B cell depletion prevented liver-metastasis clearance by anti-CTLA-4 treatment. Peritoneal metastases were devoid of B cells and TLS, while the T cells in these lesions displayed a dysfunctional phenotype. Ascites samples from patients with cancer with peritoneal metastases and from the mouse model contained significantly higher levels of IL-10, TGFb1, TGFb2 and TGFb3 than serum samples. Conclusions By combining organoid and humanized mouse technologies, we present a novel model for spontaneous multiorgan metastasis by MSI-H CRC, in which the clinically observed organ site-dependent benefit of ICB is recapitulated. Moreover, we provide empirical evidence for a critical role for B cells in the generation of site-dependent antitumor immunity following anti-CTLA-4 treatment. High levels of immunosuppressive cytokines in ascites may underlie the observed resistance of peritoneal metastases to ICB.
Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis
Authors: Meredyth G Ll Wilkinson, Dale Moulding, Thomas C R McDonnell, Michael Orford, Chris Wincup, Joanna Y J Ting, Georg W Otto, Restuadi Restuadi, Daniel Kelberman, Charalampia Papadopoulou, Sergi Castellano, Simon Eaton, Claire T Deakin, Elizabeth C Rosser, Lucy R Wedderburn
Journal: Annals of the Rheumatic Diseases (2022)

To define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM).
Infiltrative Growth Predicts the Risk of Recurrence After Surgery in Well-Differentiated Non-Functioning Pancreatic Neuroendocrine Tumors
Authors: Marco Schiavo Lena, Stefano Partelli, Valentina Andreasi, Francesca Muffatti, Miriam Redegalli, Emanuela Brunetto, Beatrice Maghini, Monika Falke, Maria Giulia Cangi, Aurel Perren, Massimo Falconi, Claudio Doglioni
Journal: Endocrine Pathology (2022)
Impact of CD4 T cells on intratumoral CD8 T-cell exhaustion and responsiveness to PD-1 blockade therapy in mouse brain tumors
Authors: Saad M Khan, Rupen Desai, Andrew Coxon, Alexandra Livingstone, Gavin P Dunn, Allegra Petti, Tanner M Johanns
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Glioblastoma is a fatal disease despite aggressive multimodal therapy. PD-1 blockade, a therapy that reinvigorates hypofunctional exhausted CD8 T cells (T ex ) in many malignancies, has not shown efficacy in glioblastoma. Loss of CD4 T cells can lead to an exhausted CD8 T-cell phenotype, and terminally exhausted CD8 T cells (T ex term ) do not respond to PD-1 blockade. GL261 and CT2A are complementary orthotopic models of glioblastoma. GL261 has a functional CD4 T-cell compartment and is responsive to PD-1 blockade; notably, CD4 depletion abrogates this survival benefit. CT2A is composed of dysfunctional CD4 T cells and is PD-1 blockade unresponsive. We leverage these models to understand the impact of CD4 T cells on CD8 T-cell exhaustion and PD-1 blockade sensitivity in glioblastoma. Methods Single-cell RNA sequencing was performed on flow sorted tumor-infiltrating lymphocytes from female C57/BL6 mice implanted with each model, with and without PD-1 blockade therapy. CD8 + and CD4 + T cells were identified and separately analyzed. Survival analyses were performed comparing PD-1 blockade therapy, CD40 agonist or combinatorial therapy. Results The CD8 T-cell compartment of the models is composed of heterogenous CD8 T ex subsets, including progenitor exhausted CD8 T cells (T ex prog ), intermediate T ex , proliferating T ex , and T ex term . GL261 is enriched with the PD-1 responsive T ex prog subset relative to the CT2A and CD4-depleted GL261 models, which are composed predominantly of the PD-1 blockade refractory T ex term subset. Analysis of the CD4 T-cell compartments revealed that the CT2A microenvironment is enriched with a suppressive T reg subset and an effector CD4 T-cell subset that expresses an inhibitory interferon-stimulated ( Isc ) signature. Finally, we demonstrate that addition of CD40 agonist to PD-1 blockade therapy improves survival in CT2A tumor-bearing mice. Conclusions Here, we describe that dysfunctional CD4 T cells are associated with terminal CD8 T-cell exhaustion, suggesting CD4 T cells impact PD-1 blockade efficacy by controlling the severity of exhaustion. Given that CD4 lymphopenia is frequently observed in patients with glioblastoma, this may represent a basis for resistance to PD-1 blockade. We demonstrate that CD40 agonism may circumvent a dysfunctional CD4 compartment to improve PD-1 blockade responsiveness, supporting a novel synergistic immunotherapeutic approach.
Digital health tools to support parents with parent-infant sleep and mental well-being
Authors: Helen L. Ball, Alice-Amber Keegan
Journal: npj Digital Medicine (2022)

Digital technology is increasingly important in people's lives, particularly for new parents as it allows them to access information, stay connected to peers and offers them seductive solutions for improving infant sleep and parental well-being. Digital technology has been developed to support parents in the following four ways: (1) providing digital information on infant sleep, (2) offering targeted support for night-time care, (3) managing infant sleep and (4) monitoring infant sleep and safety. Evidence on the effectiveness of these strategies is varied and there are concerns regarding the reliability of information, use of personal data, commercial exploitation of parents, and the effects of replacing caregiver presence with digital technology.
Impact of systemic inflammatory markers in patients with ALK-positive non-small cell lung cancer treated with crizotinib
Authors: O.F. Olmez, A. Bilici, P. Gursoy, E. Cubukcu, A. Sakin, T. Korkmaz, I. Cil, B. Cakar, S. Menekse, T. Demir, O. Acikgoz, J. Hamdard
Journal: Pulmonology (2022)

To evaluate the prognostic utility of inflammation-based prognostic scores in patients with ALK-positive metastatic or non-resectable non-small-cell lung cancer (NSCLC) treated with crizotinib. A total of 82 patients with ALK-positive metastatic or non-resectable NSCLC who received ALK TKI crizotinib were included. Pre-treatment modified Glasgow prognostic score (mGPS), prognostic nutritional index (PNI), and systemic immune-inflammation index (SII) were calculated. Multivariable logistic regression and Cox proportional hazards models were used to assess the impact of pretreatment mGPS, PNI, and SII on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). The ORR was 77.2%, while 1-year OS and PFS rates were 95.0% and 93.5%, respectively. The univariate analysis revealed significantly higher 1-year PFS (89.4 vs. 64.4%, p=0.043) and OS (92.0 vs. 83.3%, p=0.01) rates in patients with low (<934.7) vs. high (≥934.7) SII scores. Multivariate analysis revealed that PNI ≥0.09 was a significant determinant of poorer 1-year OS rates (hazard ratio [HR]: 2.46, 95% confidence interval [CI] 0.88–4.85, p=0.035). No significant difference was observed in survival rates according to gender, age, smoking status, prior lines of therapy, or mGPS scores, while higher mGPS scores (odds ratio [OR]: 0.1, 95%CI 0.16–1.04; p=0.009) and higher PNI scores (OR: 0.16, 95% CI 0.02–0.55; p=0.035) were associated with poorer ORR. Our findings indicate the prognostic significance of PNI and SII in terms of survival outcome and the impact of mGPS and PNI on treatment response in patients with ALK-positive NSCLC treated with crizotinib.
Illegal e-Cigarettes Targeting Youth
Authors: Rita Rubin
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Corrigendum to: “PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma” [J Hepatol 77 (2022) 163-176]
Authors: Chuan-Yuan Wei, Meng-Xuan Zhu, Peng-Fei Zhang, Xiao-Yong Huang, Jin-Kai Wan, Xiu-Zhong Yao, Ze-Tao Hu, Xiao-Qiang Chai, Rui Peng, Xuan Yang, Chao Gao, Jian Gao, Si-Wei Wang, Yi-Min Zheng, Zheng Tang, Qiang Gao, Jian Zhou, Jia-Bin Cai, Ai-Wu Ke, Jia Fan
Journal: Journal of Hepatology (2022)
Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer
Authors: Meng Qiao, Fei Zhou, Xinyu Liu, Tao Jiang, Haowei Wang, Yijun Jia, Xuefei Li, Chao Zhao, Lei Cheng, Xiaoxia Chen, Shengxiang Ren, Hongcheng Liu, Caicun Zhou
Journal: Journal for ImmunoTherapy of Cancer (2022)

Anti-PD-1(L1) therapies are less efficacious in patients with EGFR-mutated non-small-cell lung cancer. However, the underlying mechanism is poorly understood.The characteristics of T cells in EGFR-mutated and wild-type tumors were analyzed based on The Cancer Genome Atlas database and clinical samples. Plasma levels of 8 T-cell-related cytokines were evaluated and its association with immunotherapy efficacy were explored. Association between EGFR signaling pathway and IL-10 was examined through tumor cell lines and clinical tumor samples. In vitro restimulation model of human CD8+T cells isolated from peripheral blood was used to analyze the impact of IL-10 on T cells. Doxycycline-inducible transgenic EGFRL858R mouse models were used to investigate the efficacy of combining recombinant mouse IL-10 protein and PD-1 blockade and its underlying mechanism in vivo.EGFR-mutated tumors showed a lack of CD8+T cell infiltration and impaired CD8+T cell cytotoxic function. The incompetent CD8+T cells in EGFR-mutated tumors were characterized as absence of CD39 expression, which defined hallmarks of cytotoxic and exhausted features and could not be reinvigorated by anti-PD-1(L1) treatment. Instead, CD39 expression defined functional states of CD8+T cells and was associated with the therapeutic response of anti-PD-1(L1) therapies. Mechanically, IL-10 upregulated CD39 expression and was limited in EGFR-mutated tumors. IL-10 induced hallmarks of CD8+T cells immunity in CD39-dependent manner. Using autochthonous EGFRL858R-driven lung cancer mouse models, combining recombinant mouse IL-10 protein and PD-1 blockade optimized antitumor effects in EGFR-mutated lung tumors.Our study suggested that owing to low level of IL-10 to induce the expression of CD39 on CD8+T cells, fewer phenotypically cytotoxic and exhausted CD39+CD8+T cells in EGFR-mutated tumors could be potentially reinvigorated by anti-PD-1(L1) treatment. Hence, IL-10 could potentially serve as a cytokine-based strategy to enhance efficacy of anti-PD-1(L1) treatment in EGFR-mutated tumors.
Stress Drivers of Glucose Dynamics during Ozone Exposure Measured Using Radiotelemetry in Rats
Authors: Andres R. Henriquez, Samantha J. Snow, Thomas W. Jackson, John S. House, Alison A. Motsinger-Reif, Cavin K. Ward-Caviness, Mette C. Schladweiler, Devin I. Alewel, Colette N. Miller, Aimen K. Farraj, Mehdi S. Hazari, Rachel Grindstaff, David Diaz-Sanchez, Andrew J. Ghio, Urmila P. Kodavanti
Journal: Environmental Health Perspectives (2022)

Background: Inhaled irritant air pollutants may trigger stress-related metabolic dysfunction associated with altered circulating adrenal-derived hormones. Objectives: We used implantable telemetry in rats to assess real-time changes in circulating glucose during and after exposure to ozone and mechanistically linked responses to neuroendocrine stress hormones. Methods: First, using a cross-over design, we monitored glucose during ozone exposures (0.0, 0.2, 0.4, and 0.8 ppm) and nonexposure periods in male Wistar Kyoto rats implanted with glucose telemeters. A second cohort of unimplanted rats was exposed to ozone (0.0, 0.4 or 0.8 ppm) for 30 min, 1 h, 2 h, or 4 h with hormones measured immediately post exposure. We assessed glucose metabolism in sham and adrenalectomized rats, with or without supplementation of adrenergic/glucocorticoid receptor agonists, and in a separate cohort, antagonists. Results: Ozone (0.8 ppm) was associated with significantly higher blood glucose and lower core body temperature beginning 90 min into exposure, with reversal of effects 4–6 h post exposure. Glucose monitoring during four daily 4-h ozone exposures revealed duration of glucose increases, adaptation, and diurnal variations. Ozone-induced glucose changes were preceded by higher levels of adrenocorticotropic hormone, corticosterone, and epinephrine but lower levels of thyroid-stimulating hormone, prolactin, and luteinizing hormones. Higher glucose and glucose intolerance were inhibited in rats that were adrenalectomized or treated with adrenergic plus glucocorticoid receptor antagonists but exacerbated by agonists. Discussion: We demonstrated the temporality of neuroendocrine-stress–mediated biological sequalae responsible for ozone-induced glucose metabolic dysfunction and mechanism in a rodent model. Stress hormones assessment with real-time glucose monitoring may be useful in identifying interactions among irritant pollutants and stress-related illnesses. https://doi.org/10.1289/EHP11088
Tumor-associated neutrophils and macrophages exacerbate antidrug IgG-mediated anaphylactic reaction against an immune checkpoint inhibitor
Authors: Takahiro Arai, Tomomi Kokubo, Ruiheng Tang, Hirohito Abo, Ayu Terui, Jotaro Hirakawa, Hidetaka Akita, Hiroto Kawashima, Akihiro Hisaka, Hiroto Hatakeyama
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background With the increased use of immune checkpoint inhibitors (ICIs), side effects and toxicity are a great concern. Anaphylaxis has been identified as a potential adverse event induced by ICIs. Anaphylaxis is a life-threatening medical emergency. However, the mechanisms and factors that can potentially influence the incidence and severity of anaphylaxis in patients with cancer remain unclear. Methods Healthy, murine colon 26, CT26, breast 4T1, EMT6, and renal RENCA tumor-bearing mice were treated with an anti-PD-L1 antibody (clone 10F.9G2). Symptoms of anaphylaxis were evaluated along with body temperature and mortality. The amounts of antidrug antibody and platelet-activating factor (PAF) in the blood were quantified via ELISA and liquid chromatography-mass spectrometry (LC-MS/MS). Immune cells were analyzed and isolated using a flow cytometer and magnetic-activated cell sorting, respectively. Results Repeated administration of the anti-PD-L1 antibody 10F.9G2 to tumor-bearing mice caused fatal anaphylaxis, depending on the type of tumor model. After administration, antidrug immunoglobulin G (IgG), but not IgE antibodies, were produced, and PAF was released as a chemical mediator during anaphylaxis, indicating that anaphylaxis was caused by an IgG-dependent pathway. Anaphylaxis induced by 10F.9G2 was treated with a PAF receptor antagonist. We identified that neutrophils and macrophages were PAF-producing effector cells during anaphylaxis, and the tumor-bearing models with increased numbers of neutrophils and macrophages showed lethal anaphylaxis after treatment with 10F.9G2. Depletion of both neutrophils and macrophages using clodronate liposomes prevented anaphylaxis in tumor-bearing mice. Conclusions Thus, increased numbers of neutrophils and macrophages associated with cancer progression may be risk factors for anaphylaxis. These findings may provide useful insights into the mechanism of anaphylaxis following the administration of immune checkpoint inhibitors in human subjects.